Overall Abstract Influenza viruses are responsible for a great deal of morbidity and mortality worldwide, especially in high isk populations. Obesity has been associated with increased severity of influenza infection and decreased response to influenza vaccines in both humans and animals models. Therefore, it is vital to understand how obesity impacts influenza virus pathogenesis and prophylaxis. Recent evidence suggests that the intestinal microbiome plays a major role of immune function and initiation not only in the gastrointestinal (GI) tract but also in other distal mucosal sites, such as the respiratory tract. Indeed, the GI microbiome plays a crucial role in response to respiratory viral infections such as influenza as well as response to influenza vaccination. Interestingly, obesity is known to directly impact the gut microbiome as well as increase susceptibility to influenza infection and diminish vaccine responses. Surprisingly, co-housing obese and lean mice for six week prior to influenza infection resulted in decreased morbidity and mortality in obese animals while enhancing morbidity and mortality in the lean mice. Given that obesity is known to impact the GI microbiome, which in turn has been shown to be important for primary and vaccine-induced responses to respiratory tract infections including influenza virus, we hypothesize that altering the obese microbiome by cohousing with lean mice leads to changes in viral pathogenesis and vaccine responsiveness in the obese host. The following specific aims will test our hypothesis: 1. Determine the impact of co-housing on influenza virology and pathogenesis 2. Determine the impact of co-housing on response to influenza vaccination in the obese host 3. Is this really all a difference of microbiome between lean and obese mice? Importantly, our laboratory has the necessary expertise to accomplish the proposed aims having extensive experience with influenza research as well as the obese model. Further, we have already begun to understand the microbiome changes associated with changes in pathogenesis and vaccine responses in lean and obese animals. A unique strength of our project is access to strong core facilities at St Jude Children?s Research hospital including microbiome and animal care resources. Collectively, this ensures success of the proposed projects. This overall research plan will have tremendous impact on our ability to combat these highly prevalent human pathogens. In high risk populations